Following their oral administration, antibiotics pass through the stomach and are then absorbed in the small intestine to diffuse in the whole organism and treat the infectious outbreak site(s) for which they have been administered. All the same, a fraction of antibiotics ingested (the importance of this fraction varies with the characteristics of each antibiotic) is not absorbed and continues its progress to the colon before being eliminated in the stool.
These residual antibiotics are combined, in the large intestine, with a fraction of the antibiotics absorbed, but which are re-excreted in the digestive tract by means of biliary elimination. This fraction is of variable importance as a function of metabolism and elimination pathways for each antibiotic. Finally, for certain antibiotics, a fraction of the dose absorbed is directly eliminated from the blood through the intestinal mucosa back into the lumen of the digestive tract, a good example is known with ciprofloxacin. Thus, whether administered orally or parenterally, a residual fraction of active antibiotics is generally found in the colon. This is the case, to varying degrees, for the great majority antibiotics from the various families used in therapeutics, with the sole notable exception of antibiotics from the amino-glycoside family for which intestinal excretion is negligible. For other antibiotics, intestinal excretion of a residual antibiotic activity will have a variety of consequences, all harmful. Indeed, the colon harbors a complex and very dense bacterial ecosystem (several hundreds of different bacterial species; more than 1011 bacteria per gram of colonic content) which will be affected by the arrival of active antibiotic residues. The following can be observed:
1. Flora imbalance which is the main cause of banal diarrhea occurring following antibiotic treatments (Bartlett J. G. (2002) Clinical practice. Antibiotic associated diarrhea, New England Journal of Medicine, 346, 334). Even though this diarrhea is generally not serious and ceases rapidly, either spontaneously, or upon completion of the antibiotic treatment, it is adversely perceived by patients and adds to the discomfort of the original illness for which the antibiotic was prescribed;
2. interference with the resistance to colonization by exogenic bacteria (or “barrier effect”) with possible risk of infection, such as alimentary salmonella intoxication (Holmberg S. D. et al. (1984) Drug resistant Salmonella from animals fed antimicrobials, New England Journal of Medicine, 311, 617);
3. selection of microorganisms resistant to the antibiotic. These microorganisms can be of various types:
a) first they can be pathogenic bacteria such as for example, Clostridium difficile, a species capable of secreting toxins causing a form of colitis known as pseudomembranous colitis (Bartlett J. G. (1997) Clostridium difficile infection: pathophysiology and diagnosis, Seminar in Gastrointestinal Disease, 8, 12);
b) they can also be microorganisms that are relatively weakly pathogenic, but whose multiplication can lead to an associated infection (vaginal Candidosis or Escherichia coli resistant cystitis).
c) they can finally be non-pathogenic commensal drug-resistant bacteria whose multiplication and fecal elimination will increase dissemination of antibiotic resistance in the environment. It is well documented that antibiotic resistance genes are carried by mobile or transposable genetic elements that may contain up to 5 or 6 antibiotic resistance genes, and are readily transmitted to other bacteria, even across species. Consequently, these resistant commensal bacteria may constitute an important source leading to drug resistance for pathogenic species. This risk is currently considered seminal in terms of the disquieting character of the evolution towards drug multiresistance by numerous species pathogenic for humans.
It would be advantageous to provide drug delivery systems and methods for reducing the quantity of residual antibiotics reaching the colon following oral or parenteral antibiotic therapy. The present invention provides such drug delivery systems and methods.